tbuckley/cabot-search huggingface dataset:
Genetic Associations Between Stress-Related Disorders and Autoimmune Disease
Authors: Yu Zeng, Chen Suo, Shuyang Yao, Donghao Lu, Henrik Larsson, Brian M. D’Onofrio, Paul Lichtenstein, Fang Fang, Unnur A. Valdimarsdóttir, Huan Song
Journal: American Journal of Psychiatry (2023)

Objective: Emerging evidence supports a bidirectional phenotypic association between stress-related disorders and autoimmune disease. However, the biological underpinnings remain unclear. Here, the authors examined whether and how shared genetics contribute to the observed phenotypic associations. Methods: Based on data from 4,123,631 individuals identified from Swedish nationwide registers, familial coaggregation of stress-related disorders (any disorder or posttraumatic stress disorder [PTSD]) and autoimmune disease were initially estimated in seven cohorts with different degrees of kinship. Polygenic risk score (PRS) analyses were then performed with individual-level genotyping data from 376,871 participants in the UK Biobank study. Finally, genetic correlation analyses and enrichment analyses were performed with genome-wide association study (GWAS) summary statistics. Results: Familial coaggregation analyses revealed decreasing odds of concurrence of stress-related disorders and autoimmune disease with descending kinship or genetic relatedness between pairs of relatives; adjusted odds ratios were 1.51 (95% CI=1.09–2.07), 1.28 (95% CI=0.97–1.68), 1.16 (95% CI=1.14–1.18), and 1.01 (95% CI=0.98–1.03) for monozygotic twins, dizygotic twins, full siblings, and half cousins, respectively. Statistically significant positive associations were observed between PRSs of stress-related disorders and autoimmune disease, as well as between PRSs of autoimmune disease and stress-related disorders. GWAS summary statistics revealed a genetic correlation of 0.26 (95% CI=0.14–0.38) between these two phenotypes and identified 10 common genes and five shared functional modules, including one module related to G-protein–coupled receptor pathways. Similar analyses performed for PTSD and specific autoimmune diseases (e.g., autoimmune thyroid disease) largely recapitulated the results of the main analyses. Conclusions: This study demonstrated familial coaggregation, genetic correlation, and common biological pathways between stress-related disorders and autoimmune disease.
In HF with iron deficiency, IV ferric derisomaltose was associated with lower rates of HF hospitalization or CV death
Authors: Joseph B. Lerman, L. Kristin Newby
Journal: Annals of Internal Medicine (2023)

Source CitationKalra PR, Cleland JG, Petrie MC, et al. Intravenous ferric derisomaltose in patients with heart failure and iron deficiency in the UK (IRONMAN): an investigator-initiated, prospective, randomised, open-label, blinded-endpoint trial. Lancet. 2022;400:2199-209. https://pubmed.ncbi.nlm.nih.gov/36347265/AbstractClinical Impact RatingsGIM/FP/GP: Hospitalists: Hematology:
Can targeted nanoparticles distinguish cancer metastasis from inflammation?
Authors: Andrew S. Choi, Taylor J. Moon, Walid Abuhashim, Anubhuti Bhalotia, Huikang Qian, Kai E. Paulsen, Morgan Lorkowski, Crystal Ndamira, Ramamurthy Gopalakrishnan, Animesha Krishnamurthy, William P. Schiemann, Efstathios Karathanasis
Journal: Journal of Controlled Release (2023)
Antigen-specific B cells direct T follicular-like helper cells into lymphoid follicles to mediate Mycobacterium tuberculosis control
Authors: Rosemary V. Swanson, Ananya Gupta, Taylor W. Foreman, Lan Lu, Jose Alberto Choreno-Parra, Stanley Kimbung Mbandi, Bruce A. Rosa, Sadia Akter, Shibali Das, Mushtaq Ahmed, Maria de la Luz Garcia-Hernandez, Dhiraj K. Singh, Ekaterina Esaulova, Maxim N. Artyomov, Jennifer Gommerman, Smriti Mehra, Joaquin Zuniga, Makedonka Mitreva, Thomas J. Scriba, Javier Rangel-Moreno, Deepak Kaushal, Shabaana A. Khader
Journal: Nature Immunology (2023)
Formate overflow drives toxic folate trapping in MTHFD1 inhibited cancer cells
Authors: Alanna C. Green, Petra Marttila, Nicole Kiweler, Christina Chalkiadaki, Elisée Wiita, Victoria Cookson, Antoine Lesur, Kim Eiden, François Bernardin, Karl S. A. Vallin, Sanjay Borhade, Maeve Long, Elahe Kamali Ghahe, Julio J. Jiménez-Alonso, Ann-Sofie Jemth, Olga Loseva, Oliver Mortusewicz, Marianne Meyers, Elodie Viry, Annika I. Johansson, Ondřej Hodek, Evert Homan, Nadilly Bonagas, Louise Ramos, Lars Sandberg, Morten Frödin, Etienne Moussay, Ana Slipicevic, Elisabeth Letellier, Jérôme Paggetti, Claus Storgaard Sørensen, Thomas Helleday, Martin Henriksson, Johannes Meiser
Journal: Nature Metabolism (2023)

Abstract Cancer cells fuel their increased need for nucleotide supply by upregulating one-carbon (1C) metabolism, including the enzymes methylenetetrahydrofolate dehydrogenase–cyclohydrolase 1 and 2 (MTHFD1 and MTHFD2). TH9619 is a potent inhibitor of dehydrogenase and cyclohydrolase activities in both MTHFD1 and MTHFD2, and selectively kills cancer cells. Here, we reveal that, in cells, TH9619 targets nuclear MTHFD2 but does not inhibit mitochondrial MTHFD2. Hence, overflow of formate from mitochondria continues in the presence of TH9619. TH9619 inhibits the activity of MTHFD1 occurring downstream of mitochondrial formate release, leading to the accumulation of 10-formyl-tetrahydrofolate, which we term a ‘folate trap’. This results in thymidylate depletion and death of MTHFD2-expressing cancer cells. This previously uncharacterized folate trapping mechanism is exacerbated by physiological hypoxanthine levels that block the de novo purine synthesis pathway, and additionally prevent 10-formyl-tetrahydrofolate consumption for purine synthesis. The folate trapping mechanism described here for TH9619 differs from other MTHFD1/2 inhibitors and antifolates. Thus, our findings uncover an approach to attack cancer and reveal a regulatory mechanism in 1C metabolism.
How Materialized Oppression Contributes to Bioethics
Authors: Kadija Ferryman, J. Henry Brems
Journal: The American Journal of Bioethics (2023)

Click to increase image sizeClick to decrease image sizeThis article refers to:Materialized Oppression in Medical Tools and Technologies DISCLOSURE STATEMENTKF is a member of the institutional review board for the National Institutes of Health's All of Us Research Program and a member of the Digital Health Ethics Advisory Board for Merck KGaA. JHB has no interests to disclose.Additional informationFundingThe author(s) reported there is no funding associated with the work featured in this article.
ERS/ESICM/ESCMID/ALAT guidelines for the management of severe community-acquired pneumonia
Authors: Ignacio Martin-Loeches, Antoni Torres, Blin Nagavci, Stefano Aliberti, Massimo Antonelli, Matteo Bassetti, Lieuwe Bos, James D. Chalmers, Lennie Derde, Jan de Waele, Jose Garnacho-Montero, Marin Kollef, Carlos Luna, Rosario Menendez, Michael Niederman, Dmitry Ponomarev, Marcos Restrepo, David Rigau, Marcus J. Schultz, Emmanuel Weiss, Tobias Welte, Richard Wunderink
Journal: European Respiratory Journal (2023)

Severe community-acquired pneumonia (sCAP) is associated with high morbidity and mortality, and while European and non-European guidelines are available for community-acquired pneumonia, there are no specific guidelines for sCAP.The European Respiratory Society (ERS), European Society of Intensive Care Medicine (ESICM), European Society of Clinical Microbiology and Infectious Diseases (ESCMID) and Latin American Thoracic Association (ALAT) launched a task force to develop the first international guidelines for sCAP. The panel comprised a total of 18 European and four non-European experts, as well as two methodologists. Eight clinical questions for sCAP diagnosis and treatment were chosen to be addressed. Systematic literature searches were performed in several databases. Meta-analyses were performed for evidence synthesis, whenever possible. The quality of evidence was assessed with GRADE (Grading of Recommendations, Assessment, Development and Evaluation). Evidence to Decision frameworks were used to decide on the direction and strength of recommendations.Recommendations issued were related to diagnosis, antibiotics, organ support, biomarkers and co-adjuvant therapy. After considering the confidence in effect estimates, the importance of outcomes studied, desirable and undesirable consequences of treatment, cost, feasibility, acceptability of the intervention and implications to health equity, recommendations were made for or against specific treatment interventions.In these international guidelines, ERS, ESICM, ESCMID and ALAT provide evidence-based clinical practice recommendations for diagnosis, empirical treatment and antibiotic therapy for sCAP, following the GRADE approach. Furthermore, current knowledge gaps have been highlighted and recommendations for future research have been made.
Disclosure of Possible Trial Termination to Participants of Interventional Clinical Trials
Authors: Nora Hutchinson, Luke Gelinas, Deborah Zarin, Barbara E. Bierer
Journal: JAMA (2023)

This study evaluates a cross-section of interventional clinical trials registered on ClinicalTrials.gov with publicly available informed consent forms along with the proportion of trials that disclosed the possibility of trial termination.
Toll-Like Receptor 3 Mediates Aortic Stenosis Through a Conserved Mechanism of Calcification
Authors: Can Gollmann-Tepeköylü, Michael Graber, Jakob Hirsch, Sophia Mair, Andreas Naschberger, Leo Pölzl, Felix Nägele, Elke Kirchmair, Gerald Degenhart, Egon Demetz, Richard Hilbe, Hao-Yu Chen, James C. Engert, Anna Böhm, Nadja Franz, Daniela Lobenwein, Daniela Lener, Christiane Fuchs, Anna Weihs, Sonja Töchterle, Georg F. Vogel, Victor Schweiger, Jonas Eder, Peter Pietschmann, Markus Seifert, Florian Kronenberg, Stefan Coassin, Michael Blumer, Hubert Hackl, Dirk Meyer, Gudrun Feuchtner, Rudolf Kirchmair, Jakob Troppmair, Markus Krane, Günther Weiss, Sotirios Tsimikas, George Thanassoulis, Michael Grimm, Bernhard Rupp, Lukas A. Huber, Shen-Ying Zhang, Jean-Laurent Casanova, Ivan Tancevski, Johannes Holfeld
Journal: Circulation (2023)

Calcific aortic valve disease (CAVD) is characterized by a phenotypic switch of valvular interstitial cells to bone-forming cells. Toll-like receptors (TLRs) are evolutionarily conserved pattern recognition receptors at the interface between innate immunity and tissue repair. Type I interferons (IFNs) are not only crucial for an adequate antiviral response but also implicated in bone formation. We hypothesized that the accumulation of endogenous TLR3 ligands in the valvular leaflets may promote the generation of osteoblast-like cells through enhanced type I IFN signaling.
Cerebrospinal fluid lipoproteins inhibit α-synuclein aggregation by interacting with oligomeric species in seed amplification assays
Authors: Giovanni Bellomo, Silvia Paciotti, Luis Concha-Marambio, Domenico Rizzo, Anna Lidia Wojdaƚa, Davide Chiasserini, Leonardo Gatticchi, Linda Cerofolini, Stefano Giuntini, Chiara Maria Giulia De Luca, Yihua Ma, Carly M. Farris, Giuseppe Pieraccini, Sara Bologna, Marta Filidei, Enrico Ravera, Moreno Lelli, Fabio Moda, Marco Fragai, Lucilla Parnetti, Claudio Luchinat
Journal: Molecular Neurodegeneration (2023)

Abstract Background Aggregation of α-synuclein (α-syn) is a prominent feature of Parkinson’s disease (PD) and other synucleinopathies. Currently, α-syn seed amplification assays (SAAs) using cerebrospinal fluid (CSF) represent the most promising diagnostic tools for synucleinopathies. However, CSF itself contains several compounds that can modulate the aggregation of α-syn in a patient-dependent manner, potentially undermining unoptimized α-syn SAAs and preventing seed quantification. Methods In this study, we characterized the inhibitory effect of CSF milieu on detection of α-syn aggregates by means of CSF fractionation, mass spectrometry, immunoassays, transmission electron microscopy, solution nuclear magnetic resonance spectroscopy, a highly accurate and standardized diagnostic SAA, and different in vitro aggregation conditions to evaluate spontaneous aggregation of α-syn. Results We found the high-molecular weight fraction of CSF (&gt; 100,000 Da) to be highly inhibitory on α-syn aggregation and identified lipoproteins to be the main drivers of this effect. Direct interaction between lipoproteins and monomeric α-syn was not detected by solution nuclear magnetic resonance spectroscopy, on the other hand we observed lipoprotein-α-syn complexes by transmission electron microscopy. These observations are compatible with hypothesizing an interaction between lipoproteins and oligomeric/proto-fibrillary α-syn intermediates. We observed significantly slower amplification of α-syn seeds in PD CSF when lipoproteins were added to the reaction mix of diagnostic SAA. Additionally, we observed a decreased inhibition capacity of CSF on α-syn aggregation after immunodepleting ApoA1 and ApoE. Finally, we observed that CSF ApoA1 and ApoE levels significantly correlated with SAA kinetic parameters in n = 31 SAA-negative control CSF samples spiked with preformed α-syn aggregates. Conclusions Our results describe a novel interaction between lipoproteins and α-syn aggregates that inhibits the formation of α-syn fibrils and could have relevant implications. Indeed, the donor-specific inhibition of CSF on α-syn aggregation explains the lack of quantitative results from analysis of SAA-derived kinetic parameters to date. Furthermore, our data show that lipoproteins are the main inhibitory components of CSF, suggesting that lipoprotein concentration measurements could be incorporated into data analysis models to eliminate the confounding effects of CSF milieu on α-syn quantification efforts.
Direct Visualization of a Lymphobronchial Fistula Causing Plastic Bronchitis
Authors: Patrick Shin, Emily Bergstrom, Tauqeer Yousuf, Jadvinder Goraya
Journal: American Journal of Respiratory and Critical Care Medicine (2023)

"Direct Visualization of a Lymphobronchial Fistula Causing Plastic Bronchitis." American Journal of Respiratory and Critical Care Medicine, 208(2), pp. e3–e4
Mitochondrial DNA and the STING pathway are required for hepatic stellate cell activation
Authors: Suyavaran Arumugam, Binghua Li, Sri Lakshmi Tejaswi Boodapati, Michael H. Nathanson, Beicheng Sun, Xinshou Ouyang, Wajahat Z. Mehal
Journal: Hepatology (2023)

TGF-β induces multiple structural and functional changes in quiescent HSCs, including an increase in proliferation, mitochondrial mass, and matrix deposition. HSC transdifferentiation requires significant bioenergetic capacity, and it is not known how TGF-β-mediated transcriptional upregulation is coordinated with the bioenergetic capacity of HSCs.
A novel transcriptional signature identifies T-cell infiltration in high-risk paediatric cancer
Authors: Chelsea Mayoh, Andrew J. Gifford, Rachael Terry, Loretta M. S. Lau, Marie Wong, Padmashree Rao, Tyler Shai-Hee, Federica Saletta, Dong-Anh Khuong-Quang, Vicky Qin, Marion K. Mateos, Deborah Meyran, Katherine E. Miller, Aysen Yuksel, Emily V. A. Mould, Rachel Bowen-James, Dinisha Govender, Akanksha Senapati, Nataliya Zhukova, Natacha Omer, Hetal Dholaria, Frank Alvaro, Heather Tapp, Yonatan Diamond, Luciano Dalla Pozza, Andrew S. Moore, Wayne Nicholls, Nicholas G. Gottardo, Geoffrey McCowage, Jordan R. Hansford, Seong-Lin Khaw, Paul J. Wood, Daniel Catchpoole, Catherine E. Cottrell, Elaine R. Mardis, Glenn M. Marshall, Vanessa Tyrrell, Michelle Haber, David S. Ziegler, Orazio Vittorio, Joseph A. Trapani, Mark J. Cowley, Paul J. Neeson, Paul G. Ekert
Journal: Genome Medicine (2023)

Abstract Background Molecular profiling of the tumour immune microenvironment (TIME) has enabled the rational choice of immunotherapies in some adult cancers. In contrast, the TIME of paediatric cancers is relatively unexplored. We speculated that a more refined appreciation of the TIME in childhood cancers, rather than a reliance on commonly used biomarkers such as tumour mutation burden (TMB), neoantigen load and PD-L1 expression, is an essential prerequisite for improved immunotherapies in childhood solid cancers. Methods We combined immunohistochemistry (IHC) with RNA sequencing and whole-genome sequencing across a diverse spectrum of high-risk paediatric cancers to develop an alternative, expression-based signature associated with CD8 + T-cell infiltration of the TIME. Furthermore, we explored transcriptional features of immune archetypes and T-cell receptor sequencing diversity, assessed the relationship between CD8 + and CD4 + abundance by IHC and deconvolution predictions and assessed the common adult biomarkers such as neoantigen load and TMB. Results A novel 15-gene immune signature, Immune Paediatric Signature Score (IPASS), was identified. Using this signature, we estimate up to 31% of high-risk cancers harbour infiltrating T-cells. In addition, we showed that PD-L1 protein expression is poorly correlated with PD-L1 RNA expression and TMB and neoantigen load are not predictive of T-cell infiltration in paediatrics. Furthermore, deconvolution algorithms are only weakly correlated with IHC measurements of T-cells. Conclusions Our data provides new insights into the variable immune-suppressive mechanisms dampening responses in paediatric solid cancers. Effective immune-based interventions in high-risk paediatric cancer will require individualised analysis of the TIME.
Trends in Telehealth Visits During Pregnancy, 2018 to 2021
Authors: Mahip Acharya, Mir M. Ali, Corey J. Hayes, Cari A. Bogulski, Everett F. Magann, Hari Eswaran
Journal: JAMA Network Open (2023)

This cross-sectional study examines trends of prenatal telehealth visits in pregnancy and explores patient characteristics associated with the number of prenatal telehealth visits.
Capturing Moral Distress as a Global Phenomenon in Healthcare
Authors: Heidi Matisonn, Jantina de Vries, Jackie Hoare
Journal: The American Journal of Bioethics (2023)

Click to increase image sizeClick to decrease image sizeThis article refers to:Moral Distress: What Are We Measuring? DISCLOSURE STATEMENTNo potential conflict of interest was reported by the author(s).Additional informationFundingHM and JDV are supported by a National Institutes of Health (NIH) Fogarty International Center Federal Award. Award number: R25TW012219. Award title: Establishing an MSc in Global Health Ethics at the University of Cape Town.
Inferred immune-cell activity is an independent predictor of HER2 negative breast cancer prognosis and response to paclitaxel-based therapy in the GeparSepto trial
Authors: Peter A. Fasching, Christopher Szeto, Carsten Denkert, Stephen Benz, Karsten Weber, Patricia Spilman, Jan Budczies, Andreas Schneeweiss, Elmar Stickeler, Sabine Schmatloch, Christian Jackisch, Thomas Karn, Hans Peter Sinn, Mathias Warm, Marion van Mackelenbergh, Shahrooz Rabizadeh, Christian Schem, Ernst Heinmöller, Volkmar Mueller, Frederik Marmé, Patrick Soon-Shiong, Valentina Nekljudova, Michael Untch, Sibylle Loibl
Journal: Clinical Cancer Research (2023)

Abstract Purpose: Tumor microenvironment (TME) immune markers have been correlated with both response to neoadjuvant therapy and prognosis in patients with breast cancer. Here, immune-cell activity of breast cancer tumors was inferred by expression-based analysis to determine if it is prognostic and/or predictive of response to neoadjuvant paclitaxel-based therapy in the GeparSepto (G7) trial (NCT01583426). Experimental Design: Pre-study biopsies from 279 patients with HER2-negative breast cancer in the G7 trial underwent RNA-seq-based profiling of 104 immune-cell-specific genes to assess inferred Immune Cell Activity (iICA) of 23 immune-cell types. Hierarchical clustering was used to classify tumors as iICA “hot,” “warm,” or “cold” by comparison of iICA in the G7 cohort relative to that of 1,467 samples from a tumor database established by Nantomics LLC. Correlations between iICA cluster, pathology-assessed tumor-infiltrating lymphocytes (TIL), and hormone receptor (HR) status for pathologic complete response (pCR), disease-free survival (DFS), and overall survival (OS) were determined. Results: iICA cluster correlated with TIL levels. The highest pCR rates were observed in hot cluster tumors, and those with relatively higher TILs. Greater inferred activity of several T-cell types was significantly associated with pCR and survival. DFS and OS were prolonged in patients with hot or warm cluster tumors, the latter particularly for HR negative tumors, even if TILs were relatively low. Conclusions: Overall, TIL level better predicted pCR, but iICA cluster better predicted survival. Differences in associations between TILs, cluster, pCR, and survival were observed for HR-positive tumors versus HR-negative tumors, suggesting expanded study of the implication of these findings is warranted.
In older patients receiving aspirin, <i>H pylori</i> eradication reduced hospitalization or death due to peptic ulcer bleeding at 2.5 y
Authors: Abhilash Perisetti, Prateek Sharma
Journal: Annals of Internal Medicine (2023)

Source Citation Hawkey C, Avery A, Coupland CAC, et al; HEAT trialists. Helicobacter pylori eradication for primary prevention of peptic ulcer bleeding in older patients prescribed aspirin in primary care (HEAT): a randomised, double-blind, placebo-controlled trial. Lancet. 2022;400:1597-1606. 36335970
Estimating individual treatment effects on COPD exacerbations by causal machine learning on randomised controlled trials
Authors: Kenneth Verstraete, Iwein Gyselinck, Helene Huts, Nilakash Das, Marko Topalovic, Maarten De Vos, Wim Janssens
Journal: Thorax (2023)

Estimating the causal effect of an intervention at individual level, also called individual treatment effect (ITE), may help in identifying response prior to the intervention.We aimed to develop machine learning (ML) models which estimate ITE of an intervention using data from randomised controlled trials and illustrate this approach with prediction of ITE on annual chronic obstructive pulmonary disease (COPD) exacerbation rates.We used data from 8151 patients with COPD of the Study to Understand Mortality and MorbidITy in COPD (SUMMIT) trial (NCT01313676) to address the ITE of fluticasone furoate/vilanterol (FF/VI) versus control (placebo) on exacerbation rate and developed a novel metric, Q-score, for assessing the power of causal inference models. We then validated the methodology on 5990 subjects from the InforMing the PAthway of COPD Treatment (IMPACT) trial (NCT02164513) to estimate the ITE of FF/umeclidinium/VI (FF/UMEC/VI) versus UMEC/VI on exacerbation rate. We used Causal Forest as causal inference model.In SUMMIT, Causal Forest was optimised on the training set (n=5705) and tested on 2446 subjects (Q-score 0.61). In IMPACT, Causal Forest was optimised on 4193 subjects in the training set and tested on 1797 individuals (Q-score 0.21). In both trials, the quantiles of patients with the strongest ITE consistently demonstrated the largest reductions in observed exacerbations rates (0.54 and 0.53, p<0.001). Poor lung function and blood eosinophils, respectively, were the strongest predictors of ITE.This study shows that ML models for causal inference can be used to identify individual response to different COPD treatments and highlight treatment traits. Such models could become clinically useful tools for individual treatment decisions in COPD.
In symptomatic isolated DVT, 12 wk vs. 6 wk of rivaroxaban reduced recurrent VTE at 24 mo
Authors: Thomas G. DeLoughery
Journal: Annals of Internal Medicine (2023)

Source Citation Ageno W, Bertu L, Bucherini E, et al; RIDTS study group. Rivaroxaban treatment for six weeks versus three months in patients with symptomatic isolated distal deep vein thrombosis: randomised controlled trial. BMJ. 2022;379:e072623. 36520715
Moral Distress and Justifiable Constraints on Moral Agency
Authors: Georgina Morley, Lauren R. Sankary
Journal: The American Journal of Bioethics (2023)

Click to increase image sizeClick to decrease image sizeThis article refers to:Moral Distress: What Are We Measuring? DISCLOSURE STATEMENTNo potential conflict of interest was reported by the author(s).Additional informationFundingThe author(s) reported there is no funding associated with the work featured in this article.